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Nitrogen Mustard Induces Formation of DNA-Histone Cross-Links in Nucleosome Core Particles

Mengdi Shang1, Mengtian Ren1, Chuanzheng Zhou1

  • 1State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, College of Chemistry , Nankai University , Tianjin 300071 , China.

Chemical Research in Toxicology
|November 16, 2019
PubMed

Insights

Nitrogen mustards, used in cancer therapy, form DNA-histone cross-links, a novel finding that may explain their cell-killing effects. These DNA-protein cross-links (DPCs) are a new target for understanding chemotherapy mechanisms.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Nitrogen mustards are chemotherapy agents whose toxicity is linked to DNA damage.
  • DNA-protein cross-links (DPCs) are formed by nitrogen mustards, but DNA-histone cross-links were unobserved.
  • Nucleosome core particles (NCPs) are the basic units of chromatin.

Purpose of the Study:

  • To investigate the formation of DNA-histone cross-links induced by nitrogen mustards.
  • To determine the relative yields of different DNA lesions caused by nitrogen mustards in NCPs.
  • To identify the specific sites of DNA-histone cross-linking.

Main Methods:

  • Treatment of reconstituted nucleosome core particles (NCPs) with mechlorethamine.
  • Quantification of DNA monoalkylation, DNA interstrand cross-links, and DNA-histone cross-links.
  • Mechanistic studies using tailless histones and competitive inhibition assays.

Main Results:

  • Mechlorethamine induced DNA-histone cross-links in NCPs, alongside DNA monoalkylation and interstrand cross-links.
  • The yields of DNA lesions decreased in the order: DNA monoalkylation ≫ DNA interstrand cross-links > DNA-histone cross-links.
  • Lysine residues in histone N- and C-terminal tails were the primary sites for DNA-histone cross-link formation.

Conclusions:

  • Nitrogen mustard-induced DNA-histone cross-links can form in NCPs, suggesting potential occurrence in vivo.
  • The formation of DNA-protein cross-links, including DNA-histone cross-links, may contribute to nitrogen mustard cytotoxicity.
  • This study reveals a new mechanism for DNA damage by nitrogen mustards in the context of chromatin structure.

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